Retinoids are a group of compounds known to include retinol (Vitamin A), retinal, all-trans-retinoic acid, 13-cis-retinoic acid, and 9-cis-retinoic acid, as well as a variety of esters and similar derivatives. Many retinoids have useful skin-treatment properties. Vitamin A, for example, has long been employed for dermal treatments, particularly for the treatment of acne in a variety of its manifestations. The use of Vitamin A itself has been limited because of the toxic character of the compound when administered in excess. Vitamin A esters, such as Vitamin A palmitate, for example, are considered safer, although these materials too have substantial levels of toxicity that limits the concentrations at which the compounds can be administered. As a Vitamin A precursor, beta-carotene has also been explored, with the expectation of greater safety. The precursor is less effective, though, since beta-carotene itself is largely inactive and must be cleaved to the active Vitamin A form before the desired effects are produced. Such cleavage, however, is difficult to manage, predict, and control.
Retinal has not achieved such level of dermal use because of the instability of the compound under exposure to heat, oxygen, and ultraviolet light, which makes the compound unacceptable for most candidate uses. All-trans-retinoic acid is generally recognized as the topical product RETIN (Ortho Pharmaceuticals, Inc., a subsidiary of Johnson & Johnson), which has been approved for use in the treatment of acne vulgaris and related forms of acne. A substantial level of administration for other indications has not yet been approved, including anti-wrinkling and antiactinic treatments of the skin. All-trans-retinoic acid has been demonstrated to be irritating to the skin, producing inflammation in a substantial proportion of users. Oral doses of 13-cis retinoic acid, or ACCUTANE® (Roche Dermatologics, a Division of Hoffmann-LaRoche Inc.) have been used in severe cases of cystic acne. The compound is, however, highly teratogenic and mutagenic, and is strictly contraindicated in women of child-bearing potential.
A number of retinoids have been identified with antiaging and antiactinic properties, including esters and amides of 13-cis-retinoic acid and all-trans-retinoic acid. In many cases these compounds have activities comparable to the parent acid and comparable inflammatory and irritating characteristics, although some are known to be safer and less irritating than others (sometimes at the expense of reduced effectiveness). Such retinoids have also been shown to be of benefit in the reduction of skin cancers and precancerous lesions of the skin, although to date use for such indications have not been approved by regulatory authorities. Retinol (Vitamin A) and retinoic acid (Vitamin A acid), its isomers, and certain of its analogs are known to have beneficial effects in the treatment of acne and keratinizing skin disorders.
Chronic sun exposure has been determined to create a number of skin disorders including skin cancer, which is usually discernible by the presence of lesions known as keratoses, as well as photoaging (or dermatoheliosis) of the skin, which is characterized by wrinkling, sallowness, roughness and mottled pigmentation. Webb et al, JAMA 259, vol. 4, pgs. 527-532, 1988, reported that photoaging of the skin of middle-aged and elderly Caucasians could be improved within a 16-week period by daily topical application of a cream containing 0.1% tretinoin (all-trans-retinoic acid).
Complicating side effects complicating administration of tretinoin include skin irritation and dermatitis of several weeks duration. Thus, a method of dermal therapy that would retain the effectiveness of tretinoin, but which is essentially non-irritating would provide a much needed solution for the treatment of many skin conditions, including acne, psoriasis, photoaging, and the like. In addition, many retinoids require a 10 to 14 day treatment cycle before noticeable therapeutic results are seen. A method of dermal therapy that has a fast onset of treatment effect would be highly desirable.